Female Fisher 344 rats (n = 25) were inoculated intrapleurally with a single 20-mg dose of (JM-100) fibrous glass. The mean length (2.2 microns) and width (0.15 microns) of the fibrous glass particles was within respirable range. Following inoculation, the rats were killed at timed intervals ranging from 2 to 430 d from inoculation. The pleural histopathologic changes were independently observed by a panel of three pathologists blinded to the time elapsed from inoculation. Fibrous adhesions, nodular lesions, and grossly evident tumor were noted in 15, 2, and 1 rat, respectively. In 1 rat there were combined adhesive and nodular changes, and in 6 there were no grossly detectable abnormalities. Chronic inflammation, fibrosis, and foreign body reaction were found in 9, 18, and 10 rats, respectively. Mesothelial hyperplasia and dysplasia were observed in 16 and 9 rats, respectively. Of 16 rats with the severest degree of hyperplasia and dysplasia, 3 developed malignant mesothelioma. This study suggests that a spectrum of rat pleural mesothelial histopathologic changes occurs before development of mesothelioma. The association of severe dysplasia in 3 rats with fully developed mesothelioma suggests that there may be a gradual progression from mesothelial hyperplasia or dysplasia to mesothelioma. Multivariate analysis further suggests that gross pleural nodular lesions and dysplasia may be significantly associated with the development of mesothelioma in this experimental model.